management of volume overload hf patients by individual dsr treatment adjustment-a clinical investigation of infusate2.0

Conditions: Heart Failure; Volume Overload

Summary: this study is a multi-center, prospective, randomized (2:1), open-label study to evaluate the safety and efficacy of dsr therapy using the infusate 2.0 peritoneal solution (composed of 30% icodextrin and 10% dextrose) in diuretic resistant patients with hf and persistent volume overload.

the study will start with a non-randomized cohort in which 3 eligible subjects will be treated with infusate 2.0 on top of their usual care while all loop diuretic treatment is stopped. a peritoneal dialysis (pd) catheter will be implanted to administer the infusate 14 days post-pd catheter implantation. the infusate will be drained via the same route after up to 24 hr dwell time. this dsr process will be repeated up to daily over a treatment period of 4 weeks (d1-d28). the quantity of infusate and the duration of dwell time will be adjusted based on treatment effect and tolerability. after the treatment period, the pd catheter is removed and a 3 month safety follow-up period starts to the end of study (d29-d120). after data and safety monitoring board (dsmb) review of 30 days follow-up data (d58) of the non-randomized cohort and dsmb approval to proceed, the 2:1 randomized enrollment of up to 30 additional subjects will be opened. * dsr group (n = 20) treatment: dsr infusate 2.0 dsr is to be started 14 days post-pd catheter implantation (= d1) for a period of 4 weeks (d28) on top of optimized usual care for hf, while loop diuretic treatment is suspended. * control group (n = 10) treatment: optimized usual care for hf iv loop diuretic treatment is to be started (or continued) after a 14 days observation period (= d1) and can be continued for up to 4 weeks (d28). all subjects should then enter the 3 month safety follow-up period (d29-d120) until the end of study (d120).

Eligibility criteria:
inclusion criteria: * aged ≥18 years at screening * weight at screening ≥50 kg (110 lbs) * creatinine-based estimated glomerular filtration rate (egfr) (ckd-epi\] 2021 formula) ≥30 ml/min/1.73m² at screening * 6-hour cumulative urine sodium excretion \<100 mmol to 40 mg iv furosemide on diuretic challenge * diagnosis of symptomatic heart failure with nyha class iii or iv and daily diuretic dose ≥80 mg furosemide (or ≥20 mg torsemide or ≥1 mg bumetanide) for ≥14 days prior to screening and nt-probnp \>2000 pg/ml (or bnp \>400 pg/ml) or oral daily diuretic dose ≥160 mg furosemide (or ≥40 mg torsemide or ≥2 mg bumetanide) over the previous 14 days and ≥2 hf volume overload events within the last 6 months prior to screening or 2 hf volume overload-related hospitalizations within the last 12 months prior to screening * persistent mild to moderate volume overload with ≥2,3 kg (5 lbs) of excess hypervolemia and more than trace peripheral edema and/or jugular venous distention and/or elevated filling pressure on chronic remote pressure monitoring device * systolic blood pressure ≥90 mmhg and \<180 mmhg * receiving maximally tolerated stable doses of guideline-directed medical therapy (gdmt) * for participants of childbearing potential: negative pregnancy test and agreement to use highly effective contraception for ≥1 month prior to screening and until ≥3 months after last exposure to investigational medicinal product * for participants with intimate partners of childbearing potential: agreement to use highly effective contraception for ≥1 month prior to screening and until ≥3 months after last exposure to investigational medicinal product exclusion criteria: * reversible cause of persistent decompensation or diuretic resistance * contraindications for peritoneal dialysis (pd) or pd catheter placement * known contraindication to icodextrin use * known contraindication or intolerance or allergy to sglt2 inhibitors * current diagnosis of severe bladder dysfunction * imminent need for hospitalization * current or prior (past 6 months) use of renal replacement therapy * anemia with hemoglobin \<8 g/dl * serum sodium \<130 meq/l * severe albuminuria (urinary albumin/creatinine ratio \>1 at screening) * severe cardiac cachexia * clinically significant cirrhosis or history of clinically significant ascites (i.e., prior large volume paracentesis) or large volume ascites on imaging or exam * type 1 diabetes, uncontrolled type 2 diabetes, "brittle" diabetes or frequent hypoglycemia or severe hyperglycemic episodes requiring emergent intervention in the last 6 months * known or suspected low output hf * prior or planned heart transplant or mechanical cardiac support implantation (lvad) * history of severe hyperkalemia \> 5.5 meq/l (past 6 months) or screening plasma potassium \>4.5 meq/l * significant non-cardiac disease or comorbidities expected to reduce life expectancy to \<1 year or to interfere with safety or conduct of the study * severe restrictive or obstructive hf or hemodynamically significant, severe uncorrected stenotic valvular disease * receiving anticoagulation or antiplatelet treatment, which cannot be withheld (bridging therapy allowed) * recent myocardial infarction, cerebrovascular accident, transient ischemic attack, coronary revascularization, arrhythmia ablation, cardiac resynchronization therapy, or surgical or transcatheter valve intervention (within 90 days prior to screening) * received treatment with other investigational products or devices within 30 days of screening or 5 halflives of the previous investigational product * pregnancy or lactation

Keywords: direct sodium removal